The Baltimore Longitudinal Study of Aging (BLSA) was established in 1958 and is one the oldest prospective studies of aging in the USA and the world. The mission of the BLSA is to learn what happens to people as they get old and how to sort out changes due to aging and from those due to disease or other causes. In 1986, an autopsy program combined with comprehensive neurologic and cognitive evaluations was established in collaboration with the Johns Hopkins University Alzheimer's Disease Research Center (ADRC). Since then, 211 subjects have undergone autopsy. All brains were examined in the Division of Neuropathology of the Johns Hopkins University. After weighing and external examination, the right hemibrain is cut in 1-cm coronal slabs and a standard set of tissue blocks is removed for overnight fixation in 4% paraformaldehyde or snap freezing. The remaining coronal slabs are frozen on prechilled aluminum plates and then maintained at -80C. The left hemibrain is fixed in 10% buffered formaldehyde for at least 2 weeks and then cut coronally. For diagnostic purposes, tissue blocks are dissected from middle frontal gyrus, superior and middle temporal gyri, inferior parietal cortex, occipital cortex, cingulate gyrus, hippocampus, entorhinal cortex, amygdala, thalamus, basal ganglia, midbrain, pons, medulla, and cerebellum. We obtainin large tissue blocks containing the entire temporal lobe including hippocampus and entorhinal cortex, and a set from the brainstem and lower diencephalon containing the entire substantia nigra and locus coeruleus. The severity of neuritic plaques is assigned a semiquantitative and age-adjusted score (0, A, B, or C) according to CERAD, and the distribution of neurofibrillary tangles is assigned a stage score (0VI) according to Braak. A substantial part of our efforts has been devoted to the understanding of the morphological substrate and underlying mechanisms by which some individuals remain cognitively intact in spite of considerable AD pathology. Initially, we defined this condition as preclinical AD, but subsequently we used the term asymptomatic AD (ASYMAD), mostly because we do not know a priori whether with longer survival, these subjects would have remained clinically normal or would have eventually progressed to MCI. In the BLSA autopsy series, ASYMAD subjects represent approximately 50% of individuals with preserved cognition beyond 75 years of age. We believe that these participants are extremely important because they may represent a group of individuals resistant to the toxic effects of AD pathology. An important caveat to the interpretation of our findings is that participants in the BLSA cohort are highly educated (mean 17.4 2.3 years), a factor that may contribute to the resistance to the clinical manifestations of the disease or to brain reserve." Although it is now accepted that asymptomatic cerebral infarcts are an important cause of dementia in the elderly, the relationship between atherosclerosis per se and dementia is controversial. Specifically, it is unclear whether atherosclerosis can cause the neuritic plaques and neurofibrillary tangles that define Alzheimer neuropathology and whether atherosclerosis, a potentially reversible risk factor, can influence cognition independent of brain infarcts. We examined the relationship between systemic atherosclerosis, Alzheimer type pathology, and dementia in autopsies from 200 participants, 175 of whom had complete body autopsies. Using a quantitative analysis of atherosclerosis in the aorta, heart, and intracranial vessels, we found no relationship between the degree of atherosclerosis in any of these systems and the degree of Alzheimer type brain pathology. However, we found that the presence of intracranial but not coronary or aortic atherosclerosis significantly increased the odds of dementia, independent of cerebral infarction. Given the large number of individuals with intracranial atherosclerosis in this cohort (136/200), the population attributable risk of dementia related to intracranial atherosclerosis (independent of infarction) is substantial and potentially reversible. These results suggest that atherosclerosis of the intracranial arteries is an independent and important risk factor for dementia, potentially reversible pathways unrelated to Alzheimer pathology and stroke through which vascular changes may influence dementia risk.